The objective of the proposed research is to utilize a combined embryo culture/teratogen biotransforming system to investigate mechanisms of teratogenesis, with the goal to improve the ability of the test system to predict the relative teratogenic potential of chemically related compounds and to assist in interspecies extrapolations of teratogenesis data. A major shortcoming of most current short-term systems that test for teratogenesis in vitro is the lack of mammalian enzymes and enzyme systems that biotransform teratogenic agents in vivo. Recent experiments in our laboratories have demonstrated that rat hepatic microsomal systems can be utilized effectively in combination with rat embryo cultures and a major goal of this research is to investigate the feasibility of incorporating human hepatic enzymes into the embryo culture system such that the capacity of human hepatic enzyme systems to activate proteratogens and to inactivate proximate/ultimate teratogens will be compared to that of common experimental animals (rats, mice and rabbits) and subhuman primates (Macaca nemestrina). Metabolic profiles of hepatic biotransforming enzymes will be compared with the capacity of the system to modulate teratogenic effects in vitro. Perturbational parameters including enzyme induction, inhibition and activation will also be employed in attempts to relate the metabolic activities to teratogen-modulating effects of the enzyme preparations utilized. We will test the feasibility of using whole hepatocytes, cultered organs and other preparations (e.g., tissue slices) in the embyro culture system in attempts to more closely simulate the metabolizing systems in vivo. Finally, we will investigate the mutagen-generating capacity of the hepatic preparations in relationship to teratogen-generating capacity with the use of the Salmonella typhimurium tester system to determine correlations that may exist. The long-term research goal is to enable a prediction of the teratogenicity of environmental chemicals in human populations with short-term tests.